Glycosphingolipid (GSL) levels affect a variety of cell functions, such as growth, differentiation, adhesion between cells or between cells and matrix proteins, binding of microorganisms and viruses to cells, and metastasis of tumor cells. Glycosphingolipids (GSLs) are derived from glucosylceramide (GlcCer), and the GlcCer precursor, ceramide. GSLs and their precursors have a role in the differentiation or inhibition of cell growth (Bielawska, et al., FEBS Letters 307-211-214 (1992)) and may be involved in functioning of vitamin D3, tumor necrosis factor α, interleukins, and apoptosis (programmed cell death). The sphingols (sphingoid bases), precursors of ceramide, and products of ceramide catabolism, have also been shown to influence many cell systems, possibly by inhibiting protein kinase C (PKC).
Glucosylceramide is made on the outler leaflet of the Golgi through the action of GlcCer synthase. GlcCer is thought to be then transferred to the lumen of the Golgi for glycotransferases to be able to access GlcCer to generate more complex GSLs. The ABC transporter, multiple drug resistance protein 1 (MDR1, P-glycoprotein) is believed to promote GSL synthesis. MDR1 has been shown to translocate glucosylcermide from the cytosolic to the luminal Golgi surface.
The importance of GSL metabolism is underscored by the seriousness of disorders resulting from defects in GSL metabolizing enzymes. For example, Tay-Sachs, Gaucher's, and Fabry's diseases, resulting from enzymatic defects in the GSL degradative pathway and the accumulation of GSL in the patient, all have severe clinical manifestations. Another example of the importance of GSL function is seen in a mechanism by which blood cells, whose surfaces contain selectin, can, under certain conditions, bind to GSLs in the blood vessel walls and produce acute, life-threatening inflammation (Alon et al., J. Immunol., 54:5356-5366 (1995)).
Because of the significant impact GSLs have on several biochemical processes, there remains a need for compounds to modulate GSL synthesis and metabolism when the processes become awry, resulting in diseases and disorders. Thus, it is desirable to provide compounds and therapeutic methods to treat conditions and diseases associated with altered GSL levels and/or GSL precursor levels. The present invention provides compositions and methods that satisfies these needs and provides related advantages as well.